WO2022091029A1 - Méthodes pour abaisser le taux d'hba1c avec une combinaison d'un inhibiteur de bromodomaine bet et d'un inhibiteur du transporteur de glucose dépendant du sodium 2 - Google Patents

Méthodes pour abaisser le taux d'hba1c avec une combinaison d'un inhibiteur de bromodomaine bet et d'un inhibiteur du transporteur de glucose dépendant du sodium 2 Download PDF

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WO2022091029A1
WO2022091029A1 PCT/IB2021/060045 IB2021060045W WO2022091029A1 WO 2022091029 A1 WO2022091029 A1 WO 2022091029A1 IB 2021060045 W IB2021060045 W IB 2021060045W WO 2022091029 A1 WO2022091029 A1 WO 2022091029A1
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diabetes
hbalc
alkyl
dementia
alkoxy
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PCT/IB2021/060045
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Kenneth Eugene Lebioda
Christopher Ross Armstrong Halliday
Aziz Naeem KHAN
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Resverlogix Corp.
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Priority to EP21885493.3A priority Critical patent/EP4236957A1/fr
Priority to US18/032,876 priority patent/US20230398137A1/en
Priority to JP2023526258A priority patent/JP2023549703A/ja
Publication of WO2022091029A1 publication Critical patent/WO2022091029A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis

Definitions

  • the present disclosure relates to methods for lowering glycated hemoglobin or hemoglobin Ale (HbAlc) level (i.e., blood HbAlc level) to treat and/or prevent a diabetes-related disease or disorder by administering to a subject in need thereof, a combination of a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.
  • HbAlc hemoglobin Ale
  • HbAlc is the glycated or glucose-coated form of hemoglobin. Hemoglobin functions by transporting oxygen through the circulatory system and can become glycated or coated with glucose from the bloodstream.
  • the HbAlc test is used to evaluate glucose control; it demonstrates an average of the blood sugar level over the past 90 days (the average lifespan of a red blood cell) and is expressed as a percentage (Sherwani et al. 2016). Testing HbAlc is recognized as a standard of care for monitoring diabetes, specifically type II diabetes (T2DM) (WHO 2011).
  • HbAlc The American Diabetes Association recommends testing HbAlc for diagnosing diabetes as an alternative to fasting plasma glucose of >7.0 mmol/L which was widely used prior to the standardization of the HbAlc diagnostic test (Khan et al. 2007).
  • Nondiabetics usually fall within the 4.0% - 5.6% HbAlc range
  • prediabetics usually have HbAlc levels of 5.7% - 6.4%, while those with 6.5% or higher HbAlc levels have clinical diagnosed diabetes (American Diabetes Association 2011).
  • Diabetes, and specially type II diabetes is characterized by chronic elevated blood glucose levels (hyperglycemia) resulting from imbalanced hepatic glucose production and insulin secretion (Kharroubi and Darwish 2015).
  • Diabetes is known to be associated with several complications, such as neuropathy, nephropathy, retinopathy, and amputations, as well as comorbidities, including insulin-resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, metabolic syndrome, progressive cognitive decline, elevated blood levels of fatty acids or glycerol, hyperlipidemia including hypertriglyceridemia, obesity, muscle quality decline, muscle atrophy, and sarcopenia (Fowler 2008; Vithian and Hurel 2010; Beckman and Creager 2016; Klein et al. 1984; Rangel et al. 2016; Zheng et al. 2019; Naqvi et al. 2017; Sheth et al.
  • insulin-resistance impaired glucose homeostasis
  • hyperglycemia hyperinsulinemia
  • metabolic syndrome progressive cognitive decline
  • elevated blood levels of fatty acids or glycerol hyperlipidemia including hypertriglyceridemia, obesity, muscle quality decline, muscle atrophy,
  • HbAlc Elevated levels of HbAlc have been correlated to decreases in cognitive function, defined as multiple mental abilities, including learning, thinking, reasoning, remembering, problem solving, decision making, and attention.
  • AgeCoDe cohort of 1,342 elderly individuals which analyzed the association between HbAlc levels and the incidence of all-cause dementia and of Alzheimer’s Disease dementia, observed that HbAlc levels of >6.5% were associated with a 2.8-fold increased risk of incident all-cause dementia and Alzheimer’s Disease dementia.
  • the EPIC -Norfolk study found that the cardiovascular risk and all-cause mortality of the participants (4,662 men and 5,570 women) had continuous associations with HbAlc levels, such that a 1% increase in HbAlc was associated with an relative-risk of death from any cause of 1.24 in men and 1.28 in women independent of age, body mass index, waist-to-hip ratio, systolic blood pressure, serum cholesterol concentration, cigarette smoking, and any history of cardiovascular diseases (Khaw et al. 2004).
  • a meta-analysis of observational studies of associations between HbAlc and cardiovascular events in patients with T2DM illustrated relative risk estimate for coronary heart disease or stroke of 1.18 for each 1% increase in HbAlc (Selvin et al. 2004).
  • SGLT2 inhibitors which induce the secretion of glucose in the urine by inhibition of sodium glucose transport protein 2, have been shown to reduce HbAlc levels in patients with established cardiovascular disease, diabetes, and chronic kidney disease (Zinman et al. 2015; Neal et al. 2017; Perkovic et al. 2019; Wiviott et al. 2019).
  • SGLT2 inhibitors to reduce elevated HbAlc levels in type 2 diabetes patients has been studied in several clinical trials, such as EMPA-REG OUTCOME for empaglifozin (NCT01131676); CANVAS Program for canaglifozin (NCT01032629 and NCT01989754); and DECLARE-TIMI 58 (NCT01730534) for dapaglifozin.
  • the adjusted mean differences in HbAlc levels between patients receiving empagliflozin and those receiving placebo were -0.42% (95% CI, -0.48 to -0.36) and -0.47% (95% CI, -0.54 to -0.41), respectively; and, at week 206, the differences were -0.24% (95% CI, -0.40 to -0.08) and -0.36% (95% CI, -0.51 to -0.20), respectively (Zinman et al. 2015).
  • canaglifozin was also shown to have the ability to reduce elevated HbAlc levels, with the mean difference between the canagliflozin group and the placebo group being -0.58% (95% CI, -0.61 to -0.56) (p ⁇ 0.001) over the duration of the trial (Neal et al. 2017).
  • RVX-208 or RVX000222 is a first-in-class Bromodomain and Extra-Terminal (BET)-inhibitor (BETi) that binds selectively to the second bromodomain of BET proteins.
  • BET proteins BET proteins (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers that recognize and bind to acetylated lysines on histones 3 and 4 and on some transcription factors. Histone bound BETs recruit transcription factors and machinery to gene enhancer and promoter sites, facilitating the transcription of proximal genes. Chronic disease profoundly alters the acetylation landscape (Chen et al. 2005; Villagra et al.
  • BETonMACE Clinical Phase 3 trial
  • MACE Major Adverse Cardiac events
  • ACS Acute Coronary Syndrome
  • RVX-208 monotherapy did not demonstrate the ability to statistically reduce levels of HbAlc in T2DM patients with recent ACS in the recently completed phase 3 BETonMACE trial (Ray et al. 2020).
  • monotherapy with an SGLT2 inhibitor also did not demonstrate a statistically significant ability to reduce levels of HbAlc in T2DM patients with a recent ACS.
  • Example 2 Surprisingly, as detailed in Example 2, we found that patients treated with the combination of RVX-208 and an SGLT2 inhibitor showed pronounced reduction of HbAlc, compared to treatment with either therapy alone.
  • the summary of the results discussed below and the detailed description of the results in Example 2 demonstrate that RVX-208 or SGLT2 inhibitors by themselves did not reduce HbAlc in patients with recent ACS and T2DM.
  • apabetalone was combined with a SGLT2 inhibitor, an unexpected and statistically significant reduction of HbAlc was observed.
  • RVX-208 in combination with SGLT2 inhibitors decreased HbAlc from a median of 8.2% at baseline to a median of 7.8% at the last visit on treatment (LVT).
  • HbAlc reduction was unexpected because, as mentioned above, the patients in BETonMACE were receiving maximum tolerated statin therapy, and statin has been shown to significantly increase 14b 1 Ac levels and worsen glycemic control in both diabetic and non-diabetic patients (Ooba et al. 2016; Cui et al, 2018).
  • the HbAlc reductions reported in the SGLT2 clinical trials discussed above would also be observed in the BETonMACE patient population when combined with treatment with a compound of Formula I.
  • the SGLT2 inhibitor monotherapy among the BETonMACE patients had a median HbAlc of 8.0% at baseline and a median HbAlc of 8.2% at LVT (z.e., no reduction in median HbAlc).
  • the RVX-208 monotherapy group had a median HbAlc of 7.3% at baseline and a median HbAlc of 7.3% at LVT (z.e., also no reduction in median HbAlc).
  • the reduction in HbAlc observed when a compound of Formula I is administered with an SGLT2 inhibitor exceeded the additive effects of apabetalone and the SGLT2 inhibitor individually.
  • the technical solution provided by the present disclosure includes methods for lowering HbAlc level to treat and/or prevent a diabetes-related disease or disorder as defined herein by administering to a subject in need thereof, a combination of a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula I or la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.
  • SGLT2 sodium-glucose transport protein 2
  • Ri and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;
  • R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;
  • R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;
  • Re is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy;
  • W is selected from C and N, wherein: if W is N, then p is 0 or 1, and if W is C, then p is 1; and for W-(R 4 ) P , W is C, p is 1 and R 4 is H, or W is N and p is 0.
  • RVX-208 or RVX000222 is a representative example of Formula I.
  • the diabetes-related disease or disorder treated and/or prevented by a method of the disclosure is a diabetic comorbidity associated with elevated HbAlc levels (e.g., >6.5% + 10%).
  • comorbidities are insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, metabolic syndrome, progressive cognitive decline, elevated blood levels of fatty acids or glycerol, hyperlipidemia including hypertriglyceridemia, obesity, muscle quality decline, muscle atrophy, sarcopenia, and a combination thereof.
  • the diabetes-related disease or disorder treated and/or prevented by a method of the disclosure is a complication of diabetes associated with elevated HbAlc levels.
  • a complication of diabetes include neuropathy, nephropathy, retinopathy, amputations, and a combination thereof.
  • the diabetes-related disease or disorder treated and/or prevented by a method of the disclosure is another diabetic comorbidity associated with elevated HbAlc levels, namely dementia associated with elevated HbAlc levels.
  • dementia associated with elevated HbAlc levels include mild cognitive impairment, vascular dementia, Alzheimer’s disease dementia, Lewy body dementia, frontotemporal dementia, mixed dementia (vascular dementia and Alzheimer’s disease), and a combination thereof.
  • the compound of Formula I or la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof is administered simultaneously with a SGLT2 inhibitor.
  • the compound of Formula I or la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof is administered sequentially with the SGLT2 inhibitor.
  • the compound of Formula I or la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof is administered in a single pharmaceutical composition with the SGLT2 inhibitor.
  • the compound of Formula I or la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof and the SGLT2 inhibitor are administered as separate compositions.
  • the compound of Formula la is selected from
  • Ri and R3 are each independently selected from alkoxy, alkyl, and hydrogen;
  • R2 is selected from alkoxy, alkyl, and hydrogen
  • R5 and R7 are each independently selected from alkyl, alkoxy, and hydrogen;
  • Re is selected from alkyl, hydroxyl, and alkoxy
  • W is selected from C and N, wherein: if W is N, then p is 0 or 1, and if W is C, then p is 1; and for W-(R 4 ) P , W is C, p is 1 and R 4 is H, or W is N and p is 0.
  • the compound of Formula I or la is 2-(4-(2- hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208; RVX000222) or a pharmaceutically acceptable salt thereof.
  • the dose of 2-(4-(2-hydroxyethoxy)-3,5- dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one is between 100-300 mg per day.
  • the compound of Formula I is given once a day. In some embodiments, it is given twice a day.
  • the SGLT2 inhibitor is empagliflozin, canagliflozin, dapagliflozin, remogliflozin, ipragliflozin, bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, tofogliflozin, or HM41322.
  • the SGLT2 inhibitor is empagliflozin, canagliflozin, or dapagliflozin.
  • the SGLT2 inhibitor is dapagliflozin.
  • the dose of dapagliflozin is between 5-10 mg
  • the dose of dapagliflozin is 5 mg or 10 mg.
  • the disclosure provides methods for lowering HbAlc level to treat and/or prevent a diabetes-related disease or disorder that is a diabetic comorbidity associated with elevated HbAlc levels selected from insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, metabolic syndrome, and a combination thereof.
  • a diabetes-related disease or disorder that is a diabetic comorbidity associated with elevated HbAlc levels selected from insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, metabolic syndrome, and a combination thereof.
  • the disclosure provides methods for lowering HbAlc level to treat and/or prevent a diabetes-related disease or disorder that is a diabetic comorbidity associated with elevated HbAlc levels that is insulin resistance (impaired glucose homeostasis).
  • the disclosure provides methods for lowering HbAlc level to treat and/or prevent a diabetes-related disease or disorder that is a diabetic comorbidity associated with elevated HbAlc levels selected from hyperglycemia, hyperinsulinemia, and a combination thereof.
  • the disclosure provides methods for lowering HbAlc level to treat and/or prevent a diabetes-related disease or disorder that is a complication of diabetes associated with elevated HbAlc levels selected from neuropathy, nephropathy, retinopathy, and a combination thereof .
  • the disclosure provides methods for treating for lowering HbAlc level to treat and/or prevent a diabetes-related disease or disorder that is a diabetic comorbidity associated with elevated HbAlc levels that is dementia associated with elevated HbAlc levels selected from mild cognitive impairment, vascular dementia, Alzheimer’s disease dementia, Lewy body dementia, frontotemporal dementia, mixed dementia (vascular dementia and Alzheimer’s disease), and a combination thereof.
  • Figure 1 depicts a comparison of the median change of HbAlc from baseline to LVT in patients administered RVX-208 with SGLT2 inhibitors versus patients administered placebo with SGLT2 inhibitors.
  • Figure 2 depicts a comparison of the median change of HbAlc from baseline to LVT of HbAlc in patients administered RVX-208 with SGLT2 inhibitors versus patients administered RVX-208 without SGLT2 inhibitors.
  • Figure 3 depicts a drug interaction matrix, comparing the median change from baseline to LVT of HbAlc in patients administered RVX-208 with or without SGLT2 inhibitors.
  • Figure 4 depicts a drug interaction matrix, comparing the mean change from baseline to LVT of HbAlc in patients administered RVX-208 with or without SGLT2 inhibitors.
  • hydrate refers to a crystal form with either a stoichiometric or non-stoichiometric amount of water incorporated into the crystal structure.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-8 carbon atoms, referred to herein as (C2-Cs) alkenyl.
  • alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2 propyl 2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.
  • alkoxy refers to an alkyl group attached to an oxygen (O-alkyl).
  • Alkoxy also include an alkenyl group attached to an oxygen (“alkenyloxy”) or an alkynyl group attached to an oxygen (“alkynyloxy”) groups.
  • alkenyloxy an alkenyl group attached to an oxygen
  • alkynyloxy an alkynyl group attached to an oxygen
  • Exemplary alkoxy groups include, but are not limited to, an alkyl, alkenyl or alkynyl group of 1-8 carbon atoms, referred to herein as (Ci-Cs) alkoxy.
  • Exemplary alkoxy groups include, but are not limited to, methoxy and ethoxy.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-8 carbon atoms, referred to herein as (Ci-Cs) alkyl.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 methyl- 1 -butyl, 2-methyl- 3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 methyl- 1 -pentyl, 4-methyl-l -pentyl, 2- methyl-2-pentyl, 3-methyl-2-pentyl, 4 methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l- butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.
  • amide refers to the form NR a C(O)(Rb) or C(O)NRbRc, wherein Ra, Rb, and Rc are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
  • the amide can be attached to another group through the carbon, the nitrogen, Rb, or Rc.
  • the amide also may be cyclic, for example Rb and Rc, may be joined to form a 3- to 8-membered ring, such as 5- or 6- membered ring.
  • amide encompasses groups such as sulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versions thereof.
  • amide also encompasses an amide group attached to a carboxy group, e.g., amide-COOH or salts such as amide-COONa, an amino group attached to a carboxy group (e.g., amino-COOH or salts such as amino-COONa).
  • amine or “amino” as used herein refers to the form NRaRe or N(Rd)Re, where Rd and Re are independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocycle, and hydrogen.
  • the amino can be attached to the parent molecular group through the nitrogen.
  • the amino also may be cyclic, for example, any two of Rd and Re may be joined together or with the N to form a 3- to 12-membered ring (e.g., morpholino or piperidinyl).
  • the term amino also includes the corresponding quaternary ammonium salt of any amino group.
  • Exemplary amino groups include, but are not limited to, alkylamino groups, wherein at least one of Rd and Re is an alkyl group.
  • Rd and Re each may be optionally substituted with hydroxyl, halogen, alkoxy, ester, or amino.
  • aryl refers to a mono-, bi-, or other multi carbocyclic, aromatic ring system.
  • the aryl group can optionally be fused to one or more rings selected from aryls, cycloalkyls, and heterocyclyls.
  • aryl groups of the present disclosure can be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
  • Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • Exemplary aryl groups also include but are not limited to a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Ce) aryl.”
  • arylalkyl refers to an alkyl group having at least one aryl substituent (e.g., aryl-alkyl).
  • exemplary arylalkyl groups include, but are not limited to, arylalkyls having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "(Ce) arylalkyl.”
  • carboxylate refers to the form R g OC(O)N(Rh), R g OC(O)N(Rh)Ri, or OC(O)NRhRi, wherein R g , Rh, and Ri are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.
  • Exemplary carbamates include, but are not limited to, arylcarbamates or heteroaryl carbamates (e.g., wherein at least one of R g , Rh and Ri are independently selected from aryl and heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine).
  • carrier refers to an aryl or cycloalkyl group.
  • carboxy refers to COOH or its corresponding carboxylate salts (e.g., COONa).
  • carboxy also includes “carboxy carbonyl,” e.g., a carboxy group attached to a carbonyl group, e.g., C(O)-COOH or salts, such as C(O)-COONa.
  • cycloalkoxy refers to a cycloalkyl group attached to an oxygen.
  • cycloalkyl refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-12 carbons, or 3-8 carbons, referred to herein as "(C3-Cs)cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes.
  • Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Cycloalkyl groups can be fused to other cycloalkyl saturated or unsaturated, aryl, or heterocyclyl groups.
  • dicarboxylic acid refers to a group containing at least two carboxylic acid groups such as saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof.
  • Exemplary dicarboxylic acids include, but are not limited to, alkyl dicarboxylic acids.
  • Dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
  • Dicarboxylic acids include, but are not limited to, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(-)-malic acid, (+)/(-) tartaric acid, isophthalic acid, and terephthalic acid.
  • Dicarboxylic acids further include carboxylic acid derivatives thereof, such as anhydrides, imides, hydrazides (for example, succinic anhydride and succinimide).
  • esters refers to the structure C(O)O-, C(O)ORj, RkC(O)O-Rj, or RkC(O)O-, where O is not bound to hydrogen, and Rj and Rk can independently be selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and heterocyclyl.
  • Rk can be a hydrogen, but Rj cannot be hydrogen.
  • the ester may be cyclic, for example the carbon atom and Rj, the oxygen atom and Rk, or Rj and Rk may be joined to form a 3- to 12-membered ring.
  • exemplary esters include, but are not limited to, alkyl esters wherein at least one of Rj and Rk is alkyl, such as O-C(O) alkyl, C(O)-O-alkyl, and alkyl C(O)-O-alkyl.
  • Exemplary esters also include aryl or heteoaryl esters, e.g., wherein at least one of Rj and Rk is a heteroaryl group such as pyridine, pyridazine, pyrimidine, and pyrazine, such as a nicotinate ester.
  • Exemplary esters also include reverse esters having the structure RkC(O)O-, where the oxygen is bound to the parent molecule.
  • Exemplary reverse esters include succinate, D-argininate, L-argininate, L-lysinate and D-lysinate.
  • Esters also include carboxylic acid anhydrides and acid halides.
  • halo or halogen as used herein refer to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms. “Haloalkyls” also encompass alkenyl or alkynyl groups substituted with one or more halogen atoms.
  • heteroaryl refers to a mono-, bi-, or multi-cyclic, aromatic ring system containing one or more heteroatoms, for example, 1 to 3 heteroatoms, such as nitrogen, oxygen, and sulfur.
  • Heteroaryls can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryls can also be fused to non-aromatic rings.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, and oxazolyl.
  • Exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, wherein the ring comprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C2-C5) heteroaryl.”
  • heterocycle refers to a saturated or unsaturated 3, 4 , 5-, 6- or 7-membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Heterocycles can be aromatic (heteroaryls) or non-aromatic.
  • Heterocycles can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
  • substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocycl
  • Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles.
  • Exemplary heterocycles include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, ox
  • hydroxy and “hydroxyl” as used herein refer to -OH.
  • hydroxyalkyl refers to a hydroxy attached to an alkyl group.
  • hydroxyaryl refers to a hydroxy attached to an aryl group.
  • ketone refers to the structure C(O)-Rn (such as acetyl, C(O)CH3) or R n -C(O)-R o .
  • the ketone can be attached to another group through Rn or R o .
  • Rn and Ro can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or Rn and Ro can be joined to form a 3- to 12 membered ring.
  • phenyl refers to a 6-membered carbocyclic aromatic ring.
  • the phenyl group can also be fused to a cyclohexane or cyclopentane ring.
  • Phenyl can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.
  • thioalkyl refers to an alkyl group attached to a sulfur (S-alkyl).
  • Alkyl “alkenyl,” “alkynyl”, “alkoxy”, “amino”, and “amide” groups can be optionally substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and N.
  • the substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.
  • a suitable substitution on an optionally substituted substituent refers to a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the present disclosure or the intermediates useful for preparing them.
  • suitable substitutions include, but are not limited to: Ci-Cs alkyl, C2-C8 alkenyl or alkynyl; Ce aryl, 5- or 6-membered heteroaryl; C3-C7 cycloalkyl; Ci-Cs alkoxy; Ce aryloxy; CN; OH; oxo; halo, carboxy; amino, such as NH(Ci-Cs alkyl), N(Ci-Cs alkyl)2, NH((Ce)aryl), or N((Ce)aryl)2; formyl; ketones, such as CO(Ci-Cs alkyl), -CO((Ce aryl) esters, such as CO2(Ci-Cs alkyl) and CO2(Ce
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • compositions refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • the compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • pharmaceutically acceptable composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
  • prodrugs as used herein represents those prodrugs of the compounds of the present disclosure that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of Formula I.
  • a discussion is provided in Higuchi et al., “Prodrugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergam on Press, 1987, both of which are incorporated herein by reference.
  • salts refers to salts of acidic or basic groups that may be present in compounds used in the present compositions.
  • Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to, sulfate, citrate, matate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, -toluenesulfonate, and pamoate (
  • Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Compounds included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
  • the compounds of Formula I or la may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers.
  • stereoisomers when used herein consists of all geometric isomers, enantiomers, or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “( ⁇ )” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
  • Individual stereoisomers of compounds for use in the methods of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • Geometric isomers can also exist in the compounds of Formula I or la.
  • the present disclosure encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
  • Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration, wherein the terms “Z” and “E” are used in accordance with IUPAC standards.
  • structures depicting double bonds encompass both the E and Z isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • the arrangements of substituents around a carbocyclic ring are designated as “cis” or “trans.”
  • the term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
  • SGLT2 inhibitor refers a substance, such as a small molecule organic chemistry compound ( ⁇ 1 kDa) or a large biomolecule such as a peptide (e.g., a soluble peptide), protein (e.g., an antibody), nucleic acid (e.g., siRNA) or a conjugate combining any two or more of the foregoing, that possesses the activity of inhibiting sodium-glucose transport protein 2 (SGLT2).
  • a small molecule organic chemistry compound ⁇ 1 kDa
  • a large biomolecule such as a peptide (e.g., a soluble peptide), protein (e.g., an antibody), nucleic acid (e.g., siRNA) or a conjugate combining any two or more of the foregoing, that possesses the activity of inhibiting sodium-glucose transport protein 2 (SGLT2).
  • Non-limiting examples of SGLT2 inhibitors include empagliflozin, canagliflozin, dapagliflozin, remogliflozin, ipragliflozin, HM41322, bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, tofogliflozin, or a pharmaceutically acceptable salt of any of the foregoing.
  • SGLT2 inhibitors are disclosed in W001/027128, W004/013118, W004/080990, EP1852439A1 , WOOl/27128, WO03/099836, W02005/092877, W02006/034489, W02006/064033, W02006/117359, W02006/117360, W02007/025943, W02007/028814, W02007/031 548, W02007/093610, W02007/ 128749, W02008/049923, W02008/055870, and W02008/055940, each of which is incorporated herein by reference in its entirety.
  • treatment refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof.
  • treatment refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient.
  • treatment or “treating” refers to reducing the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
  • treatment or “treating” refers to delaying the onset or progression of a disease or disorder. For example, treating a cholesterol disorder may comprise decreasing blood cholesterol levels.
  • prevention refers to a reduction of the risk of acquiring a given disease or disorder or a symptom of a given disease or disorder.
  • “dementia associated with elevated HbAlc levels” refers to dementia, such as mild cognitive impairment, vascular dementia, Alzheimer’s disease dementia, Lewy body dementia, frontotemporal dementia, and mixed dementia (vascular dementia and Alzheimer’s disease), and a combination thereof, whereby a subject suffering therefrom has a HbAlc level in blood of >6.5% + 10% (z.e., 6.5%-7.15%), if or when measured.
  • progression of cognitive decline refers to the self-reported experience of worsening or more frequent confusion or memory loss, whereby a subject suffering therefrom has a HbAlc level in blood of >6.5% + 10%, if or when measured. It is a form of cognitive impairment and one of the earliest noticeable symptoms of Alzheimer’s disease and disease-related dementias.
  • MCI mimild cognitive impairment
  • diabetes-related disease or disorder refers to diseases, disorders and conditions that are complications of diabetes and/or comorbidities of diabetes associated with elevated HbAlc levels, whereby a subject suffering therefrom has a HbAlc level in blood of >6.5% + 10%, if or when measured.
  • Non-limiting examples of a diabetes-related disease or disorder that is a complication of diabetes or diabetic complication associated with elevated HbAlc levels are neuropathy, nephropathy, retinopathy, amputations, and a combination thereof.
  • Non-limiting examples of a diabetes-related disease or disorder that is a comorbidity of diabetes or diabetic comorbidity associated with elevated HbAlc levels are insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, metabolic syndrome, progressive cognitive decline, elevated blood levels of fatty acids or glycerol, hyperlipidemia including hypertriglyceridemia, obesity, muscle quality decline, muscle atrophy, sarcopenia, and a combination thereof.
  • Another non-limiting example of a diabetes-related disease or disorder that is a comorbidity of diabetes or diabetic comorbidity associated with elevated HbAlc levels is dementia associated with elevated HbAlc levels.
  • the present disclosure provides a method for lowering glycated hemoglobin (HbAlc) level to treat and/or prevent a diabetes-related disease or disorder, or a method for treating and/or preventing a diabetes-related disease or disorder by lowering glycated hemoglobin (HbAlc) level, the method comprising administering to a subject in need thereof, a combination of a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula I: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
  • SGLT2 sodium-glucose transport protein 2
  • Ri and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;
  • R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;
  • R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;
  • Re is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy;
  • W is selected from C and N, wherein: if W is N, then p is 0 or 1, and if W is C, then p is 1; and for W-(R 4 ) P , W is C, p is 1 and R 4 is H, or W is N and p is 0.
  • the compound of Formula I is a compound of Formula la: or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein:
  • Ri and R3 are each independently selected from alkoxy, alkyl, and hydrogen;
  • R2 is selected from alkoxy, alkyl, and hydrogen
  • R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;
  • Re is selected from alkyl, hydroxyl, and alkoxy
  • W is selected from C and N, wherein: if W is N, then p is 0 or 1, and if W is C, then p is 1; and for W-(R 4 ) P , W is C, p is 1 and R 4 is H, or W is N and p is 0.
  • the compound of Formula I or la is 2-(4-(2- hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208 or RVX000222) or a pharmaceutically acceptable salt thereof.
  • the method of the disclosure comprises administering to the subject, a daily dose of 100-300 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the method of the disclosure comprises administering to the subject, a daily dose of 200 mg of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7- dimethoxyquinazolin-4(3H)-one or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • the SGLT2 inhibitor is selected from empagliflozin, canagliflozin, dapagliflozin, bexagliflozin, ertugliflozin, sotagliflozin, luseogliflozin, tofogliflozin, and HM41322.
  • the SGLT2 inhibitor is selected from empagliflozin, canagliflozin, and dapagliflozin.
  • the compound of Formula I or la is administered simultaneously with the SGLT2 inhibitor as separate compositions.
  • the compound of Formula I or la is administered with the SGLT2 inhibitor as a single composition.
  • the subject is a human.
  • the subject is a human on statin therapy.
  • the subject is a human on high intensity or maximum tolerated statin therapy.
  • the high intensity statin treatment or therapy refers to a daily dose of at least 20 mg, or at least 40 mg, or 20-80 mg, or 20-40 mg, or 40-80 mg.
  • the maximum tolerated statin treatment or therapy refers to a daily dose of at least 40 mg, or 40 mg- 80 mg, or 80 mg.
  • the subject is on rosuvastatin therapy. In one embodiment, the subject is on atorvastatin therapy.
  • the subject is a human with type 2 diabetes and low HDL cholesterol (below 40 mg/dL for males and below 45 mg/dL for females) and a recent acute coronary syndrome (ACS) (preceding 7-90 days).
  • ACS acute coronary syndrome
  • the diabetes-related disease or disorder is a diabetic comorbidity associated with elevated HbAlc levels. In one embodiment, the diabetes-related disease or disorder is a diabetic comorbidity associated with elevated HbAlc levels that is insulin resistance (impaired glucose homeostasis). In one embodiment, the diabetes-related disease or disorder is a diabetic comorbidity associated with elevated HbAlc levels that is selected from muscle quality decline, muscle atrophy, sarcopenia, and a combination thereof. In one embodiment, the diabetes-related disease or disorder is a diabetic comorbidity associated with elevated HbAlc levels that is dementia associated with elevated HbAlc levels. In one embodiment, the dementia associated with elevated HbAlc levels is selected from mild cognitive impairment, vascular dementia, Alzheimer’s disease dementia, Lewy body dementia, frontotemporal dementia, mixed dementia (vascular dementia and Alzheimer’s disease), and a combination thereof.
  • the diabetes-related disease or disorder is a complication of diabetes associated with elevated HbAlc levels.
  • the complication of diabetes is selected from nephropathy, neuropathy, retinopathy, and a combination thereof.
  • the present disclosure provides a method for lowering glycated hemoglobin (HbAlc) level, the method comprising administering to a subject in need thereof, a combination of a sodium-glucose transport protein 2 (SGLT2) inhibitor and a compound of Formula I or Formula la or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof as defined above.
  • the method for lowering HbAlc level treats and/or prevents a diabetes-related disease or disorder.
  • Exemplary embodiments of the method for lowering HbAlc such as specific compounds of Formula I or la or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof; specific daily doses of compounds of Formula I or la or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof; specific SGLT2 inhibitors; manner of administration of compounds of Formula I or la or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof and the SGLT2 inhibitor (/. ⁇ ., simultaneously, sequentially, as separate compositions, or as a single composition); subject criteria, subject sub-populations; and specific diabetes-related diseases and disorders are as described in any one or more of the exemplary embodiments above.
  • Obesity and glycemic control in patients with diabetes mellitus Analysis of physician electronic health records in the US from 2009-2011. Journal of diabetes and its complications, 30(2), 212-220. Yoon, J. W., Ha, Y. C., Kim, K. M., Moon, J. H., Choi, S. H., Lim, S., Park, Y. J., Lim, J. Y., Kim, K. W., Park, K. S., & Jang, H. C. (2016). Hyperglycemia Is Associated with Impaired Muscle Quality in Older Men with Diabetes: The Korean Longitudinal Study on Health and Aging. Diabetes & metabolism journal, 40(2), 140-146. Kalyani, R.
  • Hyperglycemia in non-obese patients with type 2 diabetes is associated with low muscle mass: The Multicenter Study for Clarifying Evidence for Sarcopenia in Patients with Diabetes Mellitus. Journal of diabetes investigation, 10(6), 1471-1479. Abidin Oztiirk, Z. A., Tiirkbeyler, L H., Demir, Z., Bilici, M., & Kepekgi, Y. (2017). The effect of blood glucose regulation on sarcopenia parameters in obese and diabetic patients. Turkish journal of physical medicine and rehabilitation, 64(1), 72-79. Ramirez, A., Wolfsgrubera, S., Langed, C. et al. (2015).
  • Elevated HbAlc is Associated with Increased Risk of Incident Dementia in Primary Care Patients.
  • Alzheimer Dis Assoc Disord 31(1), 48-54.
  • Rawshani A. Rawshani, A., Svensson, A.-M., and Gudbjornsdottir, S.
  • Diabetologia, 58 (Suppl 1):S1— S607.
  • Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA.
  • Molecular and cellular biology 29(5), 1375-1387. Brown, J. D., Lin, C. Y., Duan, Q., Griffin, G., Federation, A., Paranal, R. M., Bair, S., Newton, G., Lichtman, A., Kung, A., Yang, T., Wang, H., Luscinskas, F. W., Croce, K., Bradner, J. E., & Plutzky, J. (2014).
  • NF-KB directs dynamic super enhancer formation in inflammation and atherogenesis.
  • Molecular cell 56(2), 219-231.
  • Apabetalone (RVX-208) was evaluated in a recently completed clinical Phase 3 trial (BETonMACE; NCT02586155) for the effect on MACE in type 2 diabetes patients with low HDL cholesterol (below 40 mg/dL for males and below 45 mg/dL for females) and a recent acute coronary syndrome (ACS) (preceding 7-90 days). All patients received high intensity statin treatment or maximum tolerated statin treatment, which was 20-40 mg daily or a maximum daily dose of 40 mg for rosuvastatin or 40-80 mg daily or a maximum daily dose of 80 mg for atorvastatin.
  • Patients (n 2425) with ACS in the preceding 7 to 90 days, with type 2 diabetes and low HDL cholesterol ( ⁇ 40 mg/dl for men, ⁇ 45 mg/dl for women), receiving intensive or maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in double-blind fashion to receive apabetalone 100 mg orally twice daily or matching placebo.
  • Baseline characteristics include female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization for index ACS (76%), treatment with dual anti-platelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg per deciliter, and median HbAlc 7.3%.
  • the primary efficacy measure is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke.
  • the study enrolled 2425 patients and the MACE outcome population consisted of 2418 patients.
  • a total of 150 patients received both RVX-208 and an SGLT2 inhibitor; a total of 148 received an SGLT2 inhibitor, but no RVX-208; a total of 1062 received RVX-208, but no SGLT2 inhibitor; a total of 1058 received neither RVX-208 or an SGLT2 inhibitor.
  • the last visit on treatment (LVT) timepoint represented the longest study exposure duration for patients receiving RVX-208 or placebo with and without SGLT2 inhibitors and is the focus of this analysis.
  • Figures 1-2 each compare the median change of HbAlc from baseline to LVT between two groups of patients, a test group, and a control group, which are described as follows: i. patients treated with a SGLT2 inhibitor and RVX-208 (test) and patients treated with a SGLT2 inhibitor only and received a placebo (control) ( Figure 1); and, ii. patients treated with RVX-208 and a SGLT2 inhibitor (test) and patients treated RVX-208 only (control) ( Figure 2).
  • RVX-208 in combination with SGLT2 inhibitors decreased HbAlc from a median of 8.2% at baseline to a median of 7.8% at the last visit on treatment (LVT).
  • the mean change of HbAlc from baseline to LVT in this combination therapy group was -0.21% (Figure 4); the median change from baseline to LVT was -0.05% ( Figure 3).
  • SGLT2 inhibitor monotherapy group had a median HbAlc of 8.0% at baseline and a median HbAlc of 8.2% at LVT.
  • the mean change from baseline to LVT in this SGLT2 inhibitor monotherapy group was +0.12% (Figure 4); the median change from baseline to LVT was +0.20% ( Figure 3).
  • the RVX-208 monotherapy group had a median HbAlc of 7.3% at baseline and a median HbAlc of 7.3% at LVT.
  • the mean change of HbAlc from baseline to LVT in this RVX-208 monotherapy group was +0.22% (Figure 4); the median change of HbAlc from baseline to LVT was +0.20% ( Figure 3).
  • the statistical parameters for the RVX-208 and SGLT2 inhibitor combination therapy are as described above.

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Abstract

L'invention concerne des méthodes pour abaisser un taux d'hémoglobine glyquée (HbA1c) pour traiter et/ou prévenir un trouble ou une maladie associée au diabète, par l'administration à un sujet en ayant besoin, d'une combinaison d'un inhibiteur de protéine de transport de sodium-glucose 2 (SGLT2) et d'un composé de Formule I ou d'un stéréoisomère, d'un tautomère, d'un sel pharmaceutiquement acceptable ou d'un hydrate de celui-ci, les variables de la Formule I étant telles que définies ici.
PCT/IB2021/060045 2020-10-30 2021-10-29 Méthodes pour abaisser le taux d'hba1c avec une combinaison d'un inhibiteur de bromodomaine bet et d'un inhibiteur du transporteur de glucose dépendant du sodium 2 WO2022091029A1 (fr)

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EP21885493.3A EP4236957A1 (fr) 2020-10-30 2021-10-29 Méthodes pour abaisser le taux d'hba1c avec une combinaison d'un inhibiteur de bromodomaine bet et d'un inhibiteur du transporteur de glucose dépendant du sodium 2
US18/032,876 US20230398137A1 (en) 2020-10-30 2021-10-29 Methods for lowering hba1c level with a combination of a bet bromodomain inhibitor and a sodium dependent glucose transport 2 inhibitor
JP2023526258A JP2023549703A (ja) 2020-10-30 2021-10-29 ＢＥＴブロモドメイン阻害剤及びナトリウム依存性グルコース輸送体２阻害剤の組み合わせを用いてＨｂＡ１ｃを低下させるための方法

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WO2010138535A1 (fr) * 2009-05-27 2010-12-02 Bristol-Myers Squibb Company Méthodes pour le traitement de diabète de type 2 chez des patients résistant à un traitement précédent avec d'autres médicaments anti-diabétiques employant un inhibiteur sglt2 et compositions associées

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4054584A4 (fr) * 2019-11-05 2023-11-08 Resverlogix Corp. Procédés de traitement et/ou de prévention d'événements cardiovasculaires indésirables majeurs (mace) avec une combinaison d'un inhibiteur de bromodomaine bet et d'un inhibiteur du transport du glucose dépendant du sodium 2

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US20230398137A1 (en) 2023-12-14
TW202233195A (zh) 2022-09-01
EP4236957A1 (fr) 2023-09-06
JP2023549703A (ja) 2023-11-29

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